tbuckley/cabot-search huggingface dataset:
CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma
Authors: Guoqing Wang, Zongliang Zhang, Kunhong Zhong, Zeng Wang, Nian Yang, Xin Tang, Hexian Li, Qizhong Lu, Zhiguo Wu, Boyang Yuan, Meijun Zheng, Ping Cheng, Aiping Tong, Liangxue Zhou
Journal: Molecular Therapy (2022)

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM. Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM.
The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway
Authors: Yi Zhang, Xiaomeng Liu, Yan Wang, Shihui Lai, Zhiqian Wang, Yudie Yang, Wenhui Liu, Hongquan Wang, Bo Tang
Journal: Molecular Cancer (2022)

Chemoresistance is a major factor contributing to the poor prognosis of patients with pancreatic cancer, and cancer stemness is one of the most crucial factors associated with chemoresistance and a very promising direction for cancer treatment. However, the exact molecular mechanisms of cancer stemness have not been completely elucidated.m6A-RNA immunoprecipitation and sequencing were used to screen m6A-related mRNAs and lncRNAs. qRT-PCR and FISH were utilized to analyse DDIT4-AS1 expression. Spheroid formation, colony formation, Western blot and flow cytometry assays were performed to analyse the cancer stemness and chemosensitivity of PDAC cells. Xenograft experiments were conducted to analyse the tumour formation ratio and growth in vivo. RNA sequencing, Western blot and bioinformatics analyses were used to identify the downstream pathway of DDIT4-AS1. IP, RIP and RNA pulldown assays were performed to test the interaction between DDIT4-AS1, DDIT4 and UPF1. Patient-derived xenograft (PDX) mouse models were generated to evaluate chemosensitivities to GEM.DDIT4-AS1 was identified as one of the downstream targets of ALKBH5, and recruitment of HuR onto m6A-modified sites is essential for DDIT4-AS1 stabilization. DDIT4-AS1 was upregulated in PDAC and positively correlated with a poor prognosis. DDIT4-AS1 silencing inhibited stemness and enhanced chemosensitivity to GEM (Gemcitabine). Mechanistically, DDIT4-AS1 promoted the phosphorylation of UPF1 by preventing the binding of SMG5 and PP2A to UPF1, which decreased the stability of the DDIT4 mRNA and activated the mTOR pathway. Furthermore, suppression of DDIT4-AS1 in a PDX-derived model enhanced the antitumour effects of GEM on PDAC.The ALKBH5-mediated m6A modification led to DDIT4-AS1 overexpression in PDAC, and DDIT-AS1 increased cancer stemness and suppressed chemosensitivity to GEM by destabilizing DDIT4 and activating the mTOR pathway. Approaches targeting DDIT4-AS1 and its pathway may be an effective strategy for the treatment of chemoresistance in PDAC.
Advancing theorizing about fast-and-slow thinking
Authors: Wim De Neys
Journal: Behavioral and Brain Sciences (2022)

Abstract Human reasoning is often conceived as an interplay between a more intuitive and deliberate thought process. In the last 50 years, influential fast-and-slow dual-process models that capitalize on this distinction have been used to account for numerous phenomena – from logical reasoning biases, over prosocial behavior, to moral decision making. The present paper clarifies that despite the popularity, critical assumptions are poorly conceived. My critique focuses on two interconnected foundational issues: the exclusivity and switch feature. The exclusivity feature refers to the tendency to conceive intuition and deliberation as generating unique responses such that one type of response is assumed to be beyond the capability of the fast-intuitive processing mode. I review the empirical evidence in key fields and show that there is no solid ground for such exclusivity. The switch feature concerns the mechanism by which a reasoner can decide to shift between more intuitive and deliberate processing. I present an overview of leading switch accounts and show that they are conceptually problematic – precisely because they presuppose exclusivity. I build on these insights to sketch the groundwork for a more viable dual-process architecture and illustrate how it can set a new research agenda to advance the field in the coming years.
Pursuing<i>FOXR2</i>-Driven Oncogenesis
Authors: Anthony P.Y. Liu, Paul A. Northcott
Journal: Cancer Research (2022)

FOXR2 encodes a Forkhead-Box transcription factor that has been recently described as a proto-oncogene. In this issue of Cancer Research, Tsai and colleagues present the first pan-cancer study summarizing the prevalence of FOXR2 overexpression beyond rare childhood-onset malignancies. Identification of a previously unknown mechanism of epigenetic activation and the expansion of FOXR2 transcriptional targets enhance the mechanistic understanding of FOXR2-driven malignancy, with the potential to uncover new therapeutic opportunities. See related article by Tsai et al., p. 2980
Single‐cell profiles reveal distinctive immune response in atopic dermatitis in contrast to psoriasis
Authors: Bowen Zhang, Lennart M. Roesner, Stephan Traidl, Valerie A. C. M. Koeken, Cheng‐Jian Xu, Thomas Werfel, Yang Li
Journal: Allergy (2022)

Understanding the complex orchestrated inflammation in atopic dermatitis (AD), one of the most common chronic inflammatory diseases worldwide, is essential for therapeutic approaches. However, a comparative analysis on the single-cell level of the inflammation signatures correlated with the severity is missing so far.We applied single-cell RNA and T-cell receptor (TCR) sequencing on immune cells enriched from skin biopsies and matched blood samples of AD in comparison with psoriasis (PS) patients.Clonally propagated skin-derived T cells showed disease-specific TCR motifs shared between patients which was more pronounced in PS compared to AD. The disease-specific T-cell clusters were mostly of a Th2/Th22 sub-population in AD and Th17/Tc17 in PS, and their numbers were associated with severity scores in both diseases. Herein, we provide for the first time a list that associates cell type-specific gene expression with the severity of the two most common chronic inflammatory skin diseases. Investigating the cell signatures in the patients´ PBMCs and skin stromal cells, a systemic involvement of type-3 inflammation was clearly detectable in PS circulating cells, while in AD inflammatory signatures were most pronounced in fibroblasts, pericytes, and keratinocytes. Compositional and functional analyses of myeloid cells revealed the activation of antiviral responses in macrophages in association with disease severity in both diseases.Different disease-driving cell types and subtypes which contribute to the hallmarks of type-2 and type-3 inflammatory signatures and are associated with disease activities could be identified by single-cell RNA-seq and TCR-seq in AD and PS.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement
Authors: David Moher, Alessandro Liberati, Jennifer Tetzlaff, Douglas G. Altman
Journal: PLoS Medicine (2009)

se ha posicionado como un centro de referencia asistencial y académica, con la proyección de conformar clínicas o centros de excelencia.Para lograr este objetivo, es indispensable que realice y se ciña a sus propias guías de práctica clínica o estándares clínicos basados en la evidencia (ECBE), que permita una adecuada y estandarizada atención de pacientes aplicando la mejor evidencia médica disponible.La obesidad es una patología de alta prevalencia en la población general, siendo uno de los motivos de consulta más
Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis
Authors: Brett L Ecker, Jasme Lee, Lily V Saadat, Thomas Aparicio, Florian E Buisman, Vinod P Balachandran, Jeffrey A Drebin, Kiyoshi Hasegawa, William R Jarnagin, Nancy E Kemeny, T Peter Kingham, Bas Groot Koerkamp, Norihiro Kokudo, Yutaka Matsuyama, Guillaume Portier, Leonard B Saltz, Kevin C Soares, Alice C Wei, Mithat Gonen, Michael I D'Angelica
Journal: The Lancet Oncology (2022)
Advanced hybrid closed loop therapy versus conventional treatment in adults with type 1 diabetes (ADAPT): a randomised controlled study
Authors: Pratik Choudhary, Ralf Kolassa, Winfried Keuthage, Jens Kroeger, Charles Thivolet, Mark Evans, Roseline Ré, Simona de Portu, Linda Vorrink, John Shin, Aklilu Habteab, Javier Castañeda, Julien da Silva, Ohad Cohen
Journal: The Lancet Diabetes & Endocrinology (2022)
Nurses: an underused, vital asset against drug-resistant infections
Authors: Enrique Castro-Sánchez, Jo Bosanquet, Molly Courtenay, Rose Gallagher, Fiona Gotterson, Elizabeth Manias, Jo McEwen, Val Ness, Rita Olans, Maria Clara Padoveze, Briette du Toit, Miquel Bennasar-Veny
Journal: The Lancet (2022)
Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial
Authors: Sophie A van den Berg, Simone M Uniken Venema, Hendrik Reinink, Jeannette Hofmeijer, Wouter J Schonewille, Irene Miedema, Puck S S Fransen, D Martijn O Pruissen, Theodora W M Raaijmakers, Gert W van Dijk, Frank-Erik de Leeuw, Jorine A van Vliet, Vincent I H Kwa, Henk Kerkhoff, Alex van 't Net, Rene Boomars, Arjen Siegers, Tycho Lok, Klaartje Caminada, Laura M Esteve Cuevas, Marieke C Visser, Casper P Zwetsloot, Jooske M F Boomsma, Mirjam H Schipper, Roeland P J van Eijkelenburg, Olvert A Berkhemer, Daan Nieboer, Hester F Lingsma, Bart J Emmer, Robert J van Oostenbrugge, Aad van der Lugt, Yvo B W E M Roos, Charles B L M Majoie, Diederik W J Dippel, Paul J Nederkoorn, H Bart van der Worp, Ayla van Ahee, Frank Visseren, Patricia Halkes, Ruben van Eijk, Michelle Simons, Wilma Pellikaan, Wilma Van Wijngaarden, Eva Ponjee, Petra Geijtenbeek, Ton Arts, Elles Zock, Wilma Oudshoorn, Frans Steenwinkel, Hamdia Samim, Mark van Zandwijk, Lisette Vrielink, Peter Jan Mulder, Aico Gerritsen, Jim Ijzermans, Marjan Kooijman, Oscar Francissen, Rick van Nuland, Wim van Zwam, Linda Jacobi, Rene van den Berg, Ludo Beenen, Adriaan van Es, Pieter-Jan van Doormaal, Geert Lycklama a Nijeholt, Ido van den Wijngaard, Albert Yoo, Lonneke Yo, Jasper Martens, Bas Hammer, Stefan Roosendaal, Anton Meijer, Menno Krietemeijer, Reinoud Bokkers, Anouk van der Hoorn, Dick Gerrits, Jonathan Coutinho, Ben Jansen, Sanne Manschot, Peter Koudstaal, Koos Keizer, Vicky Chalos, Adriaan Versteeg, Lennard Wolff, Henk van Voorst, Matthijs van der Sluijs, Arnolt-Jan Hoving, Kilian Treurniet, Natalie LeCouffe, Rob van de Graaf, Robert-Jan Goldhoorn, Wouter Hinseveld, Anne Pirson, Lotte Sondag, Manon Kappelhof, Manon Tolhuisen, Josje Brouwer, Wouter van der Steen, Leon Rinkel, Agnetha Bruggeman, Rita Sprengers, Martin Sterrenberg, Sabrina Verheesen, Leontien Heiligers, Yvonne Martens, Naziha El Ghannouti, Miranda Slotboom
Journal: The Lancet Neurology (2022)
New guidance for researching acute hepatitis in children
Authors: Priya Venkatesan
Journal: The Lancet Microbe (2022)

An excess of cases of severe acute hepatitis of unknown origin was first reported in 2022 by the UK on April 5. The UK Health Security Agency (UKHSA) announced that there were 60 cases under investigation in children younger than 10 years, and that the usual common viruses that cause hepatitis had not been detected. Such cases continued to be reported from multiple countries around the world, and between April 5 and July 8, 2022, WHO noted that 35 countries reported 1010 probable cases. Of these, 46 children (5%) have needed liver transplantations, and 22 (2%) have died.
Evasion of neutralising antibodies by omicron sublineage BA.2.75
Authors: Daniel J Sheward, Changil Kim, Julian Fischbach, Sandra Muschiol, Roy A Ehling, Niklas K Björkström, Gunilla B Karlsson Hedestam, Sai T Reddy, Jan Albert, Thomas P Peacock, Ben Murrell
Journal: The Lancet Infectious Diseases (2022)
Fibroblast GSK-3α Promotes Fibrosis via RAF-MEK-ERK Pathway in the Injured Heart
Authors: Prachi Umbarkar, Sultan Tousif, Anand P. Singh, Joshua C. Anderson, Qinkun Zhang, Michelle D. Tallquist, James Woodgett, Hind Lal
Journal: Circulation Research (2022)

Background: Heart failure is the leading cause of mortality, morbidity, and health care expenditures worldwide. Numerous studies have implicated GSK-3 (glycogen synthase kinase-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms seem to play overlapping, unique and even opposing functions in the heart. Previously, we have shown that of the 2 isoforms of GSK-3, cardiac fibroblast GSK-3β acts as a negative regulator of myocardial fibrosis in the ischemic heart. However, the role of cardiac fibroblast-GSK-3α in the pathogenesis of cardiac diseases is completely unknown. Methods: To define the role of cardiac fibroblast-GSK-3α in myocardial fibrosis and heart failure, GSK-3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn-promoter-driven Cre recombinase. Control and GSK-3α KO mice were subjected to cardiac injury and heart parameters were evaluated. The fibroblast kinome mapping was carried out to delineate molecular mechanism followed by in vivo and in vitro analysis. Results: Fibroblast-specific GSK-3α deletion restricted fibrotic remodeling and preserved function of the injured heart. We observed reductions in cell migration, collagen gel contraction, α-SMA protein levels, and expression of ECM genes in TGFβ1-treated KO fibroblasts, indicating that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, suggesting the profibrotic role of GSK-3α is SMAD3 independent. The molecular studies confirmed decreased ERK signaling in GSK-3α-KO CFs. Conversely, adenovirus-mediated expression of a constitutively active form of GSK-3α (Ad-GSK-3α S21A ) in fibroblasts increased ERK activation and expression of fibrogenic proteins. Importantly, this effect was abolished by ERK inhibition. Conclusions: GSK-3α-mediated MEK-ERK activation is a critical profibrotic signaling circuit in the injured heart, which operates independently of the canonical TGF-β1-SMAD3 pathway. Therefore, strategies to inhibit the GSK-3α-MEK-ERK signaling circuit could prevent adverse fibrosis in diseased hearts.
Chiral Hydrogel Accelerates Re‐Epithelization in Chronic Wounds via Mechanoregulation
Authors: Hanting Zhu, Chao Xing, Xiaoqiu Dou, Yu Zhao, Yinbo Peng, Chuanliang Feng, Yong Fang
Journal: Advanced Healthcare Materials (2022)

Chronic wounds, such as diabetic foot ulcers (DFU), are a serious clinical problem. It is a challenge for the conventional wound dressings to achieve the desirable therapeutic efficacy due to the lack of biomimetic structural environment for rapid re-epithelization. Inspired by the naturally existing chiral structures in skin, a novel amino acid-based chiral hydrogel dressing is developed, consisting of left-handed or right-handed helical fibers self-assembled by l/d-phenylalanine derivatives. Compared to the levorotatory chiral hydrogel (LH), the dextral chiral hydrogel (DH) shows the ability to enhance cell adhesion, proliferation, and migration, and strongly promotes diabetic wound healing and re-epithelialization with a drug-free mode. Interestingly, the dextral chiral hydrogel is able to actively increase adsorption of type I collagen and promote proliferation and migration of keratinocyte in an integrin and YAP-mediated manner. This study not only provides a novel strategy for treatment of chronic wounds by utilizing dextral chiral hydrogel dressings, but also unveils the molecular mechanism for effect of dextral chiral structures on the promoted proliferation of keratinocyte.
Characterization of Morreton virus as an oncolytic virotherapy platform for liver cancers
Authors: Bolni Marius Nagalo, Yumei Zhou, Emilien J. Loeuillard, Chelsae Dumbauld, Oumar Barro, Natalie M. Elliott, Alexander T. Baker, Mansi Arora, James M. Bogenberger, Nathalie Meurice, Joachim Petit, Pedro Luiz Serrano Uson, Faaiq Aslam, Elizabeth Raupach, Musa Gabere, Alexei Basnakian, Camila C. Simoes, Martin J. Cannon, Steven R. Post, Kenneth Buetow, Jean Christopher Chamcheu, Michael T. Barrett, Dan G. Duda, Bertram Jacobs, Richard Vile, Michael A. Barry, Lewis R. Roberts, Sumera Ilyas, Mitesh J. Borad
Journal: Hepatology (2022)

Background: Morreton virus (MORV) is an oncolytic Vesiculovirus , genetically distinct from vesicular stomatitis virus (VSV). Aim: To report that MORV induced potent cytopathic effects (CPEs) in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) in vitro models. Approach and Results: In preliminary safety analyses, high intranasal doses (up to 10 10 50% tissue culture infectious dose [TCID 50 ]) of MORV were not associated with significant adverse effects in immune competent, non–tumor‐bearing mice. MORV was shown to be efficacious in a Hep3B hepatocellular cancer xenograft model but not in a CCA xenograft HuCCT1 model. In an immune competent, syngeneic murine CCA model, single intratumoral treatments with MORV (1 × 10 7 TCID 50 ) triggered a robust antitumor immune response leading to substantial tumor regression and disease control at a dose 10‐fold lower than VSV (1 × 10 8 TCID 50 ). MORV led to increased CD8 + cytotoxic T cells without compensatory increases in tumor‐associated macrophages and granulocytic or monocytic myeloid‐derived suppressor cells. Conclusions: Our findings indicate that wild‐type MORV is safe and can induce potent tumor regression via immune‐mediated and immune‐independent mechanisms in HCC and CCA animal models without dose limiting adverse events. These data warrant further development and clinical translation of MORV as an oncolytic virotherapy platform.
Phototheranostic nanoparticles with aggregation-induced emission as a four-modal imaging platform for image-guided photothermal therapy and ferroptosis of tumor cells
Authors: Zhenjie Wang, Yuehua Wang, Heqi Gao, Chenhong Tang, Zhenzhen Feng, Ling Lin, Siyao Che, Chunmei Luo, Dan Ding, Donghui Zheng, Zhiqiang Yu, Zhenwei Peng
Journal: Biomaterials (2022)
Functional microspheres for tissue regeneration
Authors: Qian Li, Bei Chang, He Dong, Xiaohua Liu
Journal: Bioactive Materials (2022)

As a new type of injectable biomaterials, functional microspheres have attracted increasing attention in tissue regeneration because they possess some advantageous properties compared to other biomaterials, including hydrogels. A variety of bio-inspired microspheres with unique structures and properties have been developed as cellular carriers and drug delivery vehicles in recent years. In this review, we provide a comprehensive summary of the progress of functional and biodegradable microspheres that have been used for tissue regeneration over the last two decades. First, we briefly introduce the biomaterials and general methods for microsphere fabrication. Next, we focus on the newly developed technologies for preparing functional microspheres, including macroporous microspheres, nanofibrous microspheres, hollow microspheres, core-shell structured microspheres, and surface-modified functional microspheres. After that, we discuss the application of functional microspheres for tissue regeneration, specifically for bone, cartilage, dental, neural, cardiac, and skin tissue regeneration. Last, we present our perspectives and future directions of functional microspheres as injectable carriers for the future advancement of tissue regeneration.